Synthesis and In vitro Efficacy of Tetracyclic Benzothiazepines Against Blood-Stage Plasmodium falciparum and Liver-Stage P. berghei.

OBJECTIVE: A series of novel, substituted tetracyclic benzothiazepines were designed and prepared in an effort to optimize the potency of this chemical class against drug-resistant strains of the malaria parasite. METHODS: Tetracyclic benzothiazepines bearing structural modification at seven distinct positions within the structure were synthesized in Knoevenagel condensation reactions followed by sequential intermolecular thio-Michael and then intramolecular imine formation reactions. Following purification and chemical characterization, the novel compounds were tested for in vitro efficacy against blood-stage P. falciparum and liver-stage P. berghei and also for in vivo efficacy against P. berghei. RESULTS: Benzothiazepines bearing structural modification at the sulfur atom and at the three carbocycles within the molecule were successfully synthesized. The majority of analogs inhibited bloodstage P. falciparum with submicromolar IC50 values. The potency of an 8-methoxy-substituted analog 12 exceeded that of chloroquine in all three P. falciparum strains tested. The parent benzothiazepine 1 possessed liver-stage activity, inhibiting P. berghei sporozoites infecting HepG2 cells with an IC50 of 106.4 nM and an IC90 of 408.9 nM, but failed to enhance the longevity of P. berghei infected mice compared to the controls. Compounds displayed modest toxicity toward HepG2 cells and were tolerated by mice at the highest dose tested, 640 mg/kg/dose once daily for three days. CONCLUSION: The tetracyclic benzothiazepine described, which inhibits P. berghei infected hepatic cells with an IC50 of 106.4 nM, would appear to warrant further investigation. Optimization of ADME properties may be required since the most active analogs are probably excessively lipophilic.

Surgical Emphysema Following Canalplasty for Aural Exostoses.

OBJECTIVE: To describe the presentation and management of surgical emphysema involving the temporomandibular joint and deep neck following exostoses removal. PATIENT: A 60-year-old male surfer presented with hearing loss and recurrent infections in the right ear. An examination revealed obstructing bony exostoses in the right external auditory canal. He underwent right canalplasty using a postauricular approach. At 5 weeks after surgery, he presented with right otalgia, swelling of the right face and neck, and complaints of a squeaking noise in the right ear with mandibular excursions. An otomicroscopic examination demonstrated a focal area of prolapsing soft tissue along the anterior bony external auditory canal with mandibular movement. The examination also revealed palpable crepitus of the right face and neck. Computed tomography was obtained of the temporal bones and neck confirming a focal anterior canal wall defect allowing communication between the glenoid fossa and external auditory canal with subcutaneous emphysema tracking around the temporomandibular joint into the masticator, parotid, and parapharyngeal spaces. INTERVENTION: Maxillomandibular fixation for 2 weeks with revision canalplasty using a split tragal cartilage graft. RESULTS: At 6 weeks after revision surgery, the patient reported complete resolution of all symptoms. Repeat imaging demonstrated complete resolution of subcutaneous and deep neck emphysema, and the otomicroscopic examination revealed a fully epithelialized external auditory canal with no further evidence of soft tissue prolapse. CONCLUSION: Maxillomandibular fixation with autologous cartilage graft is an effective management strategy for complications of canalplasty resulting in exposure of the temporomandibular joint capsule and surgical emphysema.